Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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CA16020802

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: eb3c68df-9fa2-461a-bce2-76e53507656b

HGVS expressions

NM_001354304.2:c.499A>T

NM_000277.1:c.499A>T

NM_000277.2:c.499A>T

NM_001354304.1:c.499A>T

NM_000277.3:c.499A>T

ENST00000307000.7:c.484A>T

ENST00000549111.5:n.595A>T

ENST00000551988.5:n.530+10856A>T

ENST00000553106.5:c.499A>T

NC_000012.12:g.102866606T>A

CM000674.2:g.102866606T>A

NC_000012.11:g.103260384T>A

CM000674.1:g.103260384T>A

NC_000012.10:g.101784514T>A

NG_008690.1:g.55997A>T

NG_008690.2:g.96805A>T

Uncertain Significance

PM3_Supporting PP4 PM2

PS3 PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.499A>T (p.Asn167Tyr) variant in PAH was reported in 1 patient with PAH deficiency referred to as non-PKU HPA (120 - 600uMol/L Phe), it was detected with pathogenic variant p.Arg408Trp (PMID: 23357515). Computational evidence for this variant is conflicting; predicted to be damaging (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant was found at an extremely low frequency in gnomAD (MAF=0.00005723). Functional studies have been reported with no major impact on enzyme activity as compared to wild type (PMID: 31208052). In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3 supporting, PP4.

PM3_Supporting

This variant was detected 1 time with the pathogenic PAH variant p.Arg408Trp in a patient with PAH deficiency. It was not specified whether the patient's genotype was homozygous or compound heterozygous for the variant. PMID: 23357515

PP4

Detected in a patient with PAH deficiency referred to as non-PKU HPA (120 - 600uMol/L Phe). PMID: 23357515

PM2

At extremely low frequency in gnomAD (MAF=0.00005723), absent from 1000 genomes and ESP

PS3

Co-expression with GroEL/ES bacterial chaperones in E.coli was measured and resulted in residual enzymatic activity of 97.8% ± 27.1% which is similar to WT PAH and not significant. Oligomerization, tetramerization and dimerization was measured and resulted in enzymatic activity of 46.6% ± 11.2%, 33.2% ± 5.8% and 20.2% ± 5.8% respectively. These results are consistent with the patient's PAH deficiency phenotype referred to as non-PKU HPA (120-600uMol/L). PMID: 31208052

PP3

Conflicting predictions: Damaging in SIFT and MutationTaster, Benign in PolyPhen2

Approved on: 2020-12-07

Published on: 2021-01-15

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